Biomedical subjects

Patrick R Hof

Publications and source records attributed to Patrick R Hof.

At least 73 records · Page 4Linked to original sources

PubMed2004

The nature and effects of cortical microvascular pathology in aging and Alzheimer's disease.

Age-related and amyloid-induced pathology of the cerebral microvasculature have been implicated as potential contributing factors to the pathogenesis of Alzheimer's disease (AD). The microvasculature plays a crucial role in maintaining brain homeostasis and deterioration of its integrity may have deleterious effects on brain function in AD, possibly leading to neurofibrillary degeneration, plaque formation, and cell loss. Brain vessels possess peculiar anatomical and physiological properties owing to their role in the exchange processes of various substances between blood and brain, which are highly regulated for the maintenance of ionic homeostasis of the neuronal environment. Here we review neuropathological aspects of cortical microvessels in aging and AD in relationship to known cardiovascular risk factors and their possible impact on the cognitive decline seen in late-onset dementia.

Aging↗

PubMed2003

Cortical orofacial motor representation in Old World monkeys, great apes, and humans. I. Quantitative analysis of cytoarchitecture.

Social life in anthropoid primates is mediated by interindividual communication, involving movements of the orofacial muscles for the production of vocalization and gestural expression. Although phylogenetic diversity has been reported in the auditory and visual communication systems of primates, little is known about the comparative neuroanatomy that subserves orofacial movement. The current study reports results from quantitative image analysis of the region corresponding to orofacial representation of primary motor cortex (Brodmann's area 4) in several catarrhine primate species (Macaca fascicularis, Papio anubis, Pongo pygmaeus, Gorilla gorilla, Pan troglodytes, and Homo sapiens) using the Grey Level Index method. This cortical region has been implicated in the execution of skilled motor activities such as voluntary facial expression and human speech. Density profiles of the laminar distribution of Nissl-stained neuronal somata were acquired from high-resolution images to quantify cytoarchitectural patterns. Despite general similarity in these profiles across catarrhines, multivariate analysis showed that cytoarchitectural patterns of individuals were more similar within-species versus between-species. Compared to Old World monkeys, the orofacial representation of area 4 in great apes and humans was characterized by an increased relative thickness of layer III and overall lower cell volume densities, providing more neuropil space for interconnections. These phylogenetic differences in microstructure might provide an anatomical substrate for the evolution of greater volitional fine motor control of facial expressions in great apes and humans.

Aged↗

PubMed2003

Cortical orofacial motor representation in Old World monkeys, great apes, and humans. II. Stereologic analysis of chemoarchitecture.

This study presents a comparative stereologic investigation of neurofilament protein- and calcium-binding protein-immunoreactive neurons within the region of orofacial representation of primary motor cortex (Brodmann's area 4) in several catarrhine primate species (Macaca fascicularis, Papio anubis, Pongo pygmaeus, Gorilla gorilla, Pan troglodytes, and Homo sapiens). Results showed that the density of interneurons involved in vertical interlaminar processing (i.e., calbindin- and calretinin-immunoreactive neurons) as well pyramidal neurons that supply heavily-myelinated projections (i.e., neurofilament protein-immunoreactive neurons) are correlated with overall neuronal density, whereas interneurons making transcolumnar connections (i.e., parvalbumin-immunoreactive neurons) do not exhibit such a relationship. These results suggest that differential scaling rules apply to different neuronal subtypes depending on their functional role in cortical circuitry. For example, cortical columns across catarrhine species appear to involve a similar conserved network of intracolumnar inhibitory interconnections, as represented by the distribution of calbindin- and calretinin-immunoreactive neurons. The subpopulation of horizontally-oriented wide-arbor interneurons, on the other hand, increases in density relative to other interneuron subpopulations in large brains. Due to these scaling trends, the region of orofacial representation of primary motor cortex in great apes and humans is characterized by a greater proportion of neurons enriched in neurofilament protein and parvalbumin compared to the Old World monkeys examined. These modifications might contribute to the voluntary dexterous control of orofacial muscles in great ape and human communication.

Animal Communication↗

PubMed2003

Stereologic analysis of estrogen receptor alpha (ER alpha) expression in rat hypothalamus and its regulation by aging and estrogen.

The estrogen receptor alpha (ERalpha) in the hypothalamus plays important roles in the regulation of reproductive development, physiology, and behavior. However, the expression of the ERalpha may change during aging or in response to varying estrogen levels. The present study measured changes in the numbers of ERalpha-expressing cells in specific hypothalamic and preoptic nuclei of ovariectomized female Sprague-Dawley rats at three ages (young [3-4 months], middle-aged [10-12 months], or old [24-26 months]) and with or without estrogen replacement. Numbers of ERalpha-immunoreactive neurons were quantified in four regions relevant to reproductive function: the anteroventral periventricular nucleus (AVPV), medial preoptic nucleus (MPN), arcuate nucleus (ARH), and ventromedial nucleus (VMN), using an unbiased stereologic approach. In the AVPV and VMN, significant age-related increases in the numbers of ERalpha-expressing cells from the middle-aged to the old group were detected, and no differences were observed in the MPN and ARH, indicating that ERalpha neuron number is maintained or even elevated during aging. No significant effects of estrogen on ERalpha cell number were detected in any of the four regions studied. Therefore, ERalpha cell number in the rat hypothalamus and preoptic area changes with aging in a region-specific manner.

Aging↗

PubMed2003

Estrogen increases the number of spinophilin-immunoreactive spines in the hippocampus of young and aged female rhesus monkeys.

It is well documented that estrogen increases dendritic spine density in CA1 pyramidal cells of young female rats. However, this effect is attenuated in aged rats. We report here a quantitative analysis of estrogen effects on hippocampal spine number as visualized with antispinophilin in young (6-8 years old) and aged (19-23 years old) female rhesus monkeys, a species with a pattern of female endocrine senescence comparable to that of humans. Monkeys were ovariectomized and administered either vehicle or estradiol cypionate 3 months postovariectomy, followed by an additional dose 3 weeks later, with perfusion 24 hours after the last estrogen treatment. Immunolocalization of spinophilin, a spine-associated protein, was used for quantitative stereologic analyses of total spinophilin-immunoreactive spine numbers in CA1 stratum radiatum and the inner and outer molecular layers of dentate gyrus. In both young and aged female monkeys, the estrogen-treated groups had an increase in spinophilin-immunoreactive spines (37% in young, P <.005; 35% in aged, P <.05) compared with the untreated groups that amounted to more than 1 billion additional immunoreactive spines. The young group also showed a trend toward an estrogen-induced increase in immunoreactive spines in the dentate gyrus outer molecular layer, but this effect was not statistically significant (P =.097). We conclude that spine number in the rhesus monkey hippocampus is highly responsive to estrogen, yet, unlike the female rat, aged female rhesus monkeys retain the capacity for spine induction in response to estrogen. These data have important implications for cognitive effects of estrogen replacement in postmenopausal women and demonstrate that an estrogen replacement protocol that mimics normal physiological cycles with timed, intermittent peaks can have profound neurobiological effects.

Age Factors↗

PubMed2003

Progressive degeneration of nonphosphorylated neurofilament protein-enriched pyramidal neurons predicts cognitive impairment in Alzheimer's disease: stereologic analysis of prefrontal cortex area 9.

We performed a stereologic analysis of a subset of pyramidal neurons known to be vulnerable in Alzheimer's disease (AD) and characterized by particularly high somatodendritic levels of nonphosphorylated neurofilament protein. In the neocortex, these large pyramidal neurons reside in the deep part of layer III (layer IIIc) and the superficial part of layer V (layer Va). We focused on prefrontal cortex area 9 in elderly control cases in comparison to cases with different degrees of cognitive dysfunction. The results confirmed that these neurons are preferentially vulnerable in AD, as their numbers decrease dramatically in cases with definite dementia, correlating strongly with the severity of the disease, to a nearly complete loss (>90%) in the endstages of AD. Furthermore, a triple-labeling experimental paradigm revealed that these particular neurons are far more likely to develop neurofibrillary tangles (NFT) and do so at a faster rate than other pyramidal cells. Nonphosphorylated neurofilament protein-rich neurons also shrink considerably during formation of NFT and the largest among them are preferentially affected. Laminar differences in the severity of these effects were observed, layer Va being more severely affected, possibly correlating with the involvement of specific cortical projections. These data reveal that different populations of neurons prone to NFT formation are lost at different rates in AD, and that nonphosphorylated neurofilament protein-enriched neurons emerge as a strikingly vulnerable subpopulation of neurons. Their preferential involvement suggests that neurons providing specific corticocortical connections between association areas are at high risk for degeneration in AD.

Aged↗

PubMed2003

Glutamate receptor subunit 3 (GluR3) immunoreactivity delineates a subpopulation of parvalbumin-containing interneurons in the rat hippocampus.

Rasmussen's encephalitis is a childhood disease resulting in intractable seizures associated with hippocampal and neocortical inflammation. An autoantibody against the GluR3 subunit of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors is implicated in the pathophysiology of Rasmussen's encephalitis. AMPA receptors mediate excitatory neurotransmission in the brain and contain combinations of four subunits (GluR1-4). Although the distributions of GluR1, GluR2, and GluR4 are known in some detail, the cellular distribution of GluR3 in the mammalian brain remains to be described. We developed and characterized a GluR3-specific monoclonal antibody and quantified the cellular distribution of GluR3 in CA1 of the rat hippocampus. GluR3 immunoreactivity was detected in all pyramidal neurons and astrocytes and in most interneurons. We quantified the intensity of GluR3 immunoreactivity in interneuron subtypes defined by their calcium-binding protein content. GluR3 immunofluorescence, but not GluR1 or GluR2 immunofluorescence, was significantly elevated in somata of parvalbumin-containing interneurons compared to pyramidal somata. Strikingly, increased GluR3 immunofluorescence was not observed in calbindin- and calretinin-containing interneurons. Furthermore, 24% of parvalbumin-containing interneurons could be distinguished from surrounding neurons based on their intense GluR3 immunoreactivity. This subpopulation had significantly elevated GluR3 immunoreactivity compared to the rest of parvalbumin-containing interneurons. Electron microscopy revealed enriched GluR3 immunoreactivity in parvalbumin-containing perikarya at cytoplasmic and postsynaptic sites. Parvalbumin-containing interneurons, potent inhibitors of cortical pyramidal neurons, are vulnerable in the brains of epileptic patients. Our findings suggest that the somata of these interneurons are enriched in GluR3, which may render them vulnerable to pathological states such as epilepsy and Rasmussen's encephalitis.

Animals↗

PubMed2003

Loss and altered spatial distribution of oligodendrocytes in the superior frontal gyrus in schizophrenia.

BACKGROUND: Brain imaging, molecular genetic, and ultrastructural evidence indicate the existence of pathologic alterations in the cortical and subcortical white matter of schizophrenic patients. METHODS: We performed a stereologic analysis of numbers, densities, and spatial distribution of oligodendrocytes in layer III and in the gyral white matter of Brodmann's area 9 in the superior frontal gyrus to assess whether these cells are affected in schizophrenia. Counts were obtained on Nissl-stained materials and on sections immunolabeled for the oligodendrocyte marker 2',3'-cyclic nucleotide-3'-phosphodiesterase (CNPase) in seven schizophrenic and seven age-matched control cases. RESULTS: A 28% decrease in total numbers (or densities) of cortical layer III oligodendrocytes and a 27% decrease in the white matter were detected in schizophrenic compared with control cases based on CNPase immunostaining. Nissl and CNPase immunohistochemistry yielded comparable results. The spatial distribution of oligodendrocytes in area 9 white matter exhibited a less clustered arrangement in schizophrenic cases. CONCLUSIONS: These results suggest a severe pathology of oligodendrocytes in schizophrenia and provide a quantitative cellular correlate of the white matter changes observed by brain imaging in vivo, showing reduced fractional anisotropy in schizophrenia. The data support recent evidence that several genes encoding myelin-related proteins consistently exhibit reduced expression in schizophrenia.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗

PubMed2003

Lewy body densities in the entorhinal and anterior cingulate cortex predict cognitive deficits in Parkinson's disease.

Previous studies reported an association between cortical Lewy body (LB) formation and dementia in Parkinson's disease (PD). However, it is unclear whether cognitive decline in this disorder is related to specific patterns of LB distribution within the cerebral cortex. Moreover, the prediction of cognitive status based on concomitant assessment of LB and Alzheimer's disease lesions has led to conflicting results. We performed a clinicopathological study in 22 elderly PD patients in whom parkinsonism preceded cognitive decline by at least 3 years. Cognitive status was assessed prospectively using the clinical dementia rating scale (CDR); quantitative assessment of LB, neurofibrillary tangles (NFT), and senile plaques (SP) was performed in Brodmann areas 9, 21, 24, 40 and the entorhinal cortex. Statistical analysis was performed using both correlation coefficients and logistic regression models. There was a highly significant correlation between CDR scores and regional LB scores in the entorhinal cortex and area 24. LB and SP densities in the entorhinal cortex accounted for 36.2% and 19.3% of the variability in CDR scores. LB densities in area 24 could explain 25.2% of this variability. NFT densities did not predict cognitive status. In multivariate models only LB densities in the entorhinal cortex and anterior cingulate cortex were significantly associated with CDR scores. These results imply that an assessment of LB pathology limited to the entorhinal cortex and area 24 may be sufficient to predict cognition in PD. They also suggest that LB formation in limbic areas may be crucial for the development of PD dementia.

Age Distribution↗

PubMed2003

Hyperbaric oxygen reduces neuronal death and improves neurological outcome after canine cardiac arrest.

BACKGROUND AND PURPOSE: Studies suggest that hyperbaric oxygen (HBO) is neuroprotective after experimental cerebral ischemia, but the mechanism is unknown. This study tested the hypotheses that postischemic HBO affords clinical and histopathological neuroprotection after experimental cardiac arrest and resuscitation (A/R) and that this neuroprotection results from improved cerebral oxygen metabolism after A/R. METHODS: Anesthetized adult female beagles underwent A/R and randomization to HBO (2.7-atm absolute [ATA] for 60 minutes, 1 hour after A/R) or control (Po2=80 to 100 mm Hg; 1 ATA). Animals underwent neurological deficit scoring (NDS) 23 hours after A/R. After euthanasia at 24 hours, neuronal death (necrotic and apoptotic) in representative animals was determined stereologically in hippocampus and cerebral neocortex. In experiment 2, arterial and sagittal sinus oxygenation and cerebral blood flow (CBF) were measured. Cerebral oxygen extraction ratio (ERc), oxygen delivery (Do2c), and metabolic rate for oxygen (CMRo2) were calculated (baseline and 2, 30, 60, 120, 180, 240, 300, and 360 minutes after restoration of spontaneous circulation). RESULTS: NDS improved after A/R in HBO animals (HBO, 35+/-14; controls, 54+/-15; P=0.028). Histopathological examination revealed significantly fewer dying neurons in HBO animals; the magnitude of neuronal injury correlated well with NDS. HBO corrected elevations in ERc (peak, 60+/-14% for controls, 26+/-4% for HBO) but did not increase Do2c or CMRo2, which decreased approximately 50% after A/R in both groups. CONCLUSIONS: HBO inhibits neuronal death and improves neurological outcome after A/R; the mechanism of HBO neuroprotection is not due to stimulation of oxidative cerebral energy metabolism.

Animals↗

PubMed2003

White matter changes in schizophrenia: evidence for myelin-related dysfunction.

Numerous lines of inquiry implicate connectivity as a central abnormality in schizophrenia. Myelination and factors that affect myelination, such as the function of oligodendroglia, are critical processes that could profoundly affect neuronal connectivity, especially given the diffuse distribution of oligodendrocytes and the widespread distribution of brain regions that have been implicated in schizophrenia. Multiple lines of evidence now converge to implicate oligodendroglia and myelin in schizophrenia. Imaging and neurocytochemical evidence, similarities with demyelinating diseases, age-related changes in white matter, myelin-related gene abnormalities, and morphologic abnormalities in the oligodendroglia demonstrated in schizophrenic brains are all examined in light of the hypothesis that oligodendroglial dysfunction and even death, with subsequent abnormalities in myelin maintenance and repair, contribute to the schizophrenic syndrome.

Age Factors↗

PubMed2003

Stereologic characterization and spatial distribution patterns of Betz cells in the human primary motor cortex.

Betz cells are giant motoneurons located in layer Vb of the primate primary motor cortex. We conducted stereological analyses of Betz cells and neighboring pyramidal cells from the brains of six neurologically normal elderly humans to determine their volume, total number, and spatial distribution, and to relate these data to functional localization. The distribution of cellular volumes exhibits a bimodal pattern, delineating two different subpopulations. Betz cell volumes follow a mediolateral gradient, the largest Betz cells being located on the most medial part of the motor cortex. Additionally, the shape of Betz cells varies between the rostral and caudal parts of the primary motor cortex, supporting the notion that there are anatomically distinct zones in primary motor cortex. The total number of Betz cells per hemisphere accounts for about one-tenth of the total number of pyramidal cells in layer Vb. Analysis of spatial distribution using Voronoi tessellation revealed maximal clustering of Betz cells in a zone situated two-thirds from the midline along the mediolateral axis of the primary motor cortex. These data suggest that Betz cells have a discrete subregional distribution that may correspond to certain aspects of the functional parcellation of area 4. These results may offer a histological correlate of functional imaging studies and are relevant in the context of neurodegenerative diseases such as amyotrophic lateral sclerosis, progressive supranuclear palsy, and Guamanian amyotrophic lateral sclerosis/Parkinsonism-dementia, and in studies of normal brain aging.

Aged↗

PubMed2003

Variability of Broca's area homologue in African great apes: implications for language evolution.

The cortical circuits subserving neural processing of human language are localized to the inferior frontal operculum and the posterior perisylvian region. Functional language dominance has been related to anatomical asymmetry of Broca's area and the planum temporale. The evolutionary history of these asymmetric patterns, however, remains obscure. Although testing of hypotheses about the evolution of language areas requires comparison to homologous regions in the brains of our closest living relatives, the great apes, to date little is known about normal interindividual variation of these regions in this group. Here we focus on Brodmann's area 44 in African great apes (Pan troglodytes and Gorilla gorilla). This area corresponds to the pars opercularis of the inferior frontal gyrus (IFG), and has been shown to exhibit both gross and cytoarchitectural asymmetries in humans. We calculated frequencies of sulcal variations and mapped the distribution of cytoarchitectural area 44 to determine whether its boundaries occurred at consistent macrostructural landmarks. A considerable amount of variation was found in the distribution of the inferior frontal sulci among great ape brains. The inferior precentral sulcus in particular was often bifurcated, which made it impossible to determine the posterior boundary of the pars opercularis. In addition, the distribution of Brodmann's area 44 showed very little correspondence to surface anatomy. We conclude that gross morphologic patterns do not offer substantive landmarks for the measurement of Brodmann's area 44 in great apes. Whether or not Broca's area homologue of great apes exhibits humanlike asymmetry can only be resolved through further analyses of microstructural components.

Africa↗

PubMed2003

Automated reconstruction of three-dimensional neuronal morphology from laser scanning microscopy images.

Experimental and theoretical studies demonstrate that both global dendritic branching topology and fine spine geometry are crucial determinants of neuronal function, its plasticity and pathology. Importantly, simulation studies indicate that the interaction between local and global morphologic properties is pivotal in determining dendritic information processing and the induction of synapse-specific plasticity. The ability to reconstruct and quantify dendritic processes at high resolution is therefore an essential prerequisite to understanding the structural determinants of neuronal function. Existing methods of digitizing 3D neuronal structure use interactive manual computer tracing from 2D microscopy images. This method is time-consuming, subjective and lacks precision. In particular, fine details of dendritic varicosities, continuous dendritic taper, and spine morphology cannot be captured by these systems. We describe a technique for automated reconstruction of 3D neuronal morphology from multiple stacks of tiled confocal and multiphoton laser scanning microscopy (CLSM and MPLSM) images. The system is capable of representing both global and local structural variations, including gross dendritic branching topology, dendritic varicosities, and fine spine morphology with sufficient resolution for accurate 3D morphometric analyses and realistic biophysical compartment modeling. Our system provides a much needed tool for automated digitization and reconstruction of 3D neuronal morphology that reliably captures detail on spatial scales spanning several orders of magnitude, that avoids the subjective errors that arise during manual tracing with existing digitization systems, and that runs on a standard desktop workstation.

Animals↗

PubMed2003

Repeated restraint stress suppresses neurogenesis and induces biphasic PSA-NCAM expression in the adult rat dentate gyrus.

Chronic restraint stress has been shown to induce structural remodelling throughout the interconnected dentate gyrus-CA3 fields. To find out how this stressor affects the rate of adult hippocampal neurogenesis, we subjected rats to acute or chronic restraint stress and assessed the proliferation, survival and differentiation of newly born cells in the dentate gyrus. We also examined polysialylated neural cell adhesion molecule expression, a molecule normally expressed in immature neurons and important for morphological plasticity. The results show that acute restraint stress did not change either the proliferation of dentate gyrus precursor cells or the expression of polysialylated neural cell adhesion molecule, whereas 3 weeks of chronic restraint stress suppressed proliferation by 24% and increased polysialylated neural cell adhesion molecule expression by 40%. The study was extended for an additional 3 weeks to trace the survival and development of the cells born after the initial 3 weeks of restraint. Rats subjected to 6 weeks of daily restraint stress exhibited suppressed cell proliferation and attenuated survival of the recently born cells after the extended time course, resulting in a 47% reduction of granule cell neurogenesis. Furthermore, 6 weeks of chronic stress significantly reduced the total number of granule cells by 13% and the granule cell layer volume by 5%. Expression of polysialylated neural cell adhesion molecule followed a biphasic time course, displaying a significant up-regulation after 3 weeks of daily restraint stress that was lost after 6 weeks of stress. These studies may help us understand the basis for hippocampal shrinkage and raise questions about the ultimate reversibility of the effects of chronic stress.

Animals↗

PubMed2003

Age-related dendritic and spine changes in corticocortically projecting neurons in macaque monkeys.

Alterations in neuronal morphology occur in primate cerebral cortex during normal aging, vary depending on the neuronal type, region and cortical layer, and have been related to memory and cognitive impairment. We analyzed how such changes affect a specific subpopulation of cortical neurons forming long corticocortical projections from the superior temporal cortex to prefrontal area 46. These neurons were identified by retrograde transport in young and old macaque monkeys. Dendritic arbors of retrogradely labeled neurons were visualized in brain slices by intracellular injection of Lucifer Yellow, and reconstructed three-dimensionally using computer-assisted morphometry. Total dendritic length, numbers of segments, numbers of spines, and spine density were analyzed in layer III pyramidal neurons forming the projection considered. Sholl analysis was used to determine potential age-related changes in dendritic complexity. We observed statistically significant age-related decreases in spine numbers and density on both apical and basal dendritic arbors in these projection neurons. On apical dendrites, changes in spine numbers occurred mainly on the proximal dendrites but spine density decreased uniformly among the different branch orders. On basal dendrites, spine numbers and density decreased preferentially on distal branches. Regressive dendritic changes were observed only in one particular portion of the apical dendrites, with the general dendritic morphology and extent otherwise unaffected by aging. In view of the fact that there is no neuronal loss in neocortex and hippocampus in old macaque monkeys, it is possible that the memory and cognitive decline known to occur in these animals is related to rather subtle changes in the morphological and molecular integrity of neurons subserving identifiable neocortical association circuits that play a critical role in cognition.

Aging↗

PubMed2003

Stereologic evidence for persistence of viable neurons in layer II of the entorhinal cortex and the CA1 field in Alzheimer disease.

The entorhinal cortex and hippocampus are the first cortical regions to be affected by the degenerative cellular process that leads to Alzheimer disease (AD) and display a limited degree of neuronal alterations in normal aging. Several quantitative studies have reported a substantial loss of neurons in these regions and a parallel increase in the number of neurofibrillary tangles (NFTs). However, accurate quantitative data on the dynamics of NFT formation are lacking. Here, we performed a stereologic assessment of the proportions of intracellular and extracellular (ghost) NFTs (iNFTs and eNFTs, respectively) and unaffected neurons in layer II of the entorhinal cortex and in the pyramidal cell layer of the CA1 field of the hippocampus in elderly control cases compared to cases with varying degrees of cognitive dysfunction. The data revealed differential rates of formation of iNFTs and eNFTs between the 2 regions and confirmed the presence of a severe disease-associated, but not age-related, neuronal loss. They also revealed that large numbers of neurons may persist either unaffected or in a transitional stage of NFT formation until the late stages of AD progression. These neurons with viability potential constitute 73% of the total numbers of profiles in layer II of the entorhinal cortex and 77% in the CA1 field in cases with a Clinical Dementia Rating score of 3. Whereas it is not possible in the present study to assess how functional such neurons with altered physiology might be, it is nonetheless likely that these transitional neurons open new options for potential therapeutic interventions aimed at protecting neurons vulnerable to neurofibrillary degeneration.

Aged↗

PubMed2003

Hippocampal and entorhinal cortex neurofibrillary tangle formation in Guamanian Chamorros free of overt neurologic dysfunction.

Since first described, amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) of Guam has represented an important model of age-related neurodegenerative disease. ALS/PDC is characterized neuropathologically by severe widespread involvement by neurofibrillary tangles (NFTs). Over the past 30 years there has been a dramatic decrease in the incidence of ALS and a 10-year increase in the age of onset of ALS and PDC. In 1979, Anderson et al reported evidence of significant NFT involvement in Guam natives who had been free of evidence of neurologic dysfunction. Using the slides from this study, we re-examined the extent of hippocampus and entorhinal NFT involvement and compared it to brains recently obtained from neurologically intact Guam natives and age-matched controls from New York. The tendency towards hippocampal and entorhinal NFT formation continues to be encountered among the inhabitants of Guam, particularly among those over age 50. although severe involvement was less commonly noted in relatively young individuals (< 50 years). As noted by Anderson et al, the pattern of neuropathologic lesions seen in those with extensive NFT involvement suggests that such cases represent preclinical examples of ALS/PDC in individuals who have yet to accumulate a sufficient burden of pathology to attract clinical attention and diagnostic evaluation.

Adolescent↗